The present invention relates to novel amino acid derivatives and to their preparation and use.
Endothelin is a peptide which is composed of 21 amino acids and which is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms ET-1, ET-2 and ET-3. xe2x80x9cEndothelinxe2x80x9d or xe2x80x9cETxe2x80x9d hereinafter means one or all endothelin isoforms. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. It is known that this vasoconstriction is caused by binding of endothelin to its receptor (Nature 332 (1988) 411-415; FEBS Letters 231 (1988) 440-444, and Biochem. Biophys. Res. Commun. 154 (1988) 868-875).
Elevated or abnormal release of endothelin causes a persistent vasoconstriction in the peripheral, renal and cerebral blood vessels, which may lead to illnesses. As reported in the literature, elevated plasma endothelin levels are found in patients with hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud""s syndrome, atherosclerosis and in the airways of asthmatics (Japan J. Hypertension 12 (1989) 79, J. Vascular Med. Biology 2 (1990) 207, J. Am. Med. Association 264 (1990) 2868).
Accordingly, substances which specifically inhibit the binding of endothelin to the receptor ought also to antagonize the various abovementioned physiological effects of endothelin and therefore be valuable drugs.
We have found that certain amino acid derivatives are good inhibitors of endothelin receptors.
The invention relates to amino acid derivatives of the formula I 
where R is formyl, tetrazolyl, cyano, COOH or a radical which can be hydrolyzed to COOH, for example R is 
where R1 has the following meanings:
a) hydrogen
b) succinimedyl
c) a 5-membered heteroaromatic ring which is linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one or two halogen atoms or one or two C1-C4-alkyl or one or two C1-C4-alkoxy groups;
d) R1 is furthermore 
xe2x80x83where k can assume the values 0, 1 and 2, p can assume the values 1, 2, 3 and 4, and R9 is C1-C4-alkyl, C3-C7-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or unsubstituted or substituted phenyl which can be substituted by one or more, eg. from one to three, of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, C1-C4-alkylamino, C1-C4-dialkylamino;
e) R1 is furthermore OR10 where R10 is: hydrogen, the cation of an alkali metal such as lithium, sodium, potassium or the cation of an alkaline earth metal such as calcium, magnesium and barium, and physiologically tolerated alkylammonium ion or the ammonium ion,
C3-C8-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
C1-C8-alkyl, in particular C1-C4-alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl;
CH2-phenyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, C1-C4-alkylamino, C1-C4-dialkylamino,
C3-C6-alkenyl or C3-C6-alkynyl, it being possible for these groups in turn to carry from one to five halogen atoms;
R10 can furthermore be a phenyl radical which can carry from one to five halogen atoms and/or from one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, amino, C1-C4-alkylamino, C1-C4-dialkylamino;
a 5-membered heteroaromatic ring which is linked via a nitrogen atom and contains from one to three nitrogen atoms and can carry one or two halogen atoms and/or one or two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenyl, C1-C4-haloalkoxy and/or C1-C4-alkylthio, in particular 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3,4-dichloro-1-imidazolyl;
f) R1 is furthermore 
xe2x80x83where R1 is: C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl as mentioned above in particular, it being possible for these radicals to carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical as mentioned above;
phenyl which is unsubstituted or substituted, in particular as mentioned above;
g) R1 is 
xe2x80x83where R12 has the same meaning as R11;
h) R1 can furthermore be 
xe2x80x83where R13 and R14 can be identical or different and have the following meanings:
hydrogen, C1-C7-alkyl, C3-C7-cycloalkyl, C3-C7-alkenyl, C3-C7-alkynyl, benzyl, phenyl, unsubstituted or substituted, as described above,
or R13 and R14 together form a C4-C7-alkylene chain which is closed to form a ring and is unsubstituted or substituted, eg. by C1-C4-alkyl, and which may contain a hetero atom, eg. oxygen, nitrogen or sulfur, such as xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, xe2x80x94(CH2)7xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Sxe2x80x94(CH2)2xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)2xe2x80x94NHxe2x80x94(CH2)2xe2x80x94;
a tetrazole group or a nitrile group.
The other substituents have the following meanings:
W is nitrogen or Cxe2x80x94NO2, and W can furthermore be a CH group when one or more of the substituents R2, R3, R15 and/or R16 are nitro;
R2 is hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, hydroxyl, mercapto, C1-C4-alkylthio, nitro, amino, C1-C4-alkylamino or C1-C4-dialkylamino, cyano, phenyl, unsubstituted or mono- to trisubstituted by halogen, hydroxyl, amino, mono- or dialkyl-(C1-C3)-amino, C1-C3-alkyl, C1-C3-alkoxy, mercapto or C1-C3-alkylthio; or a five- or six-membered heteroaromatic ring which contains from one to three nitrogen atoms and/or one sulfur or oxygen atom and which carries from one to three substituents as described above;
R2 can furthermore form with the adjacent carbon atom and X a 5- or 6-membered alkylene or alkylidene ring in which, in each case, one or two carbon atoms can be replaced by a hetero atom such as nitrogen, sulfur or oxygen, and which can be mono- to trisubstituted by the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-alkylthio, amino, C1-C3-alkylamino, C1-C3-dialkylamino;
X is nitrogen or CR15 where R15 is hydrogen or C1-C5-alkyl, C1-C5-alkoxy, C1-C5-alkylthio, nitro, phenyl, hydroxyl, mercapto, halogen, amino, C1-C4-alkylamino, C1-C4-dialkylamino or cyano,
or CR15 is linked to R2 to form a 5- or 6-membered ring as described above, and furthermore CR15 can form together with R3 and its adjacent carbon atom a 5- or 6-membered ring as described above;
R3 can have the same meaning as R2 and furthermore form together with the adjacent carbon atom and Y a 5- or 6-membered alkylene or alkylidene ring in which, in each case, one or two carbon atoms can be replaced by nitrogen, oxygen or sulfur; the 5- or 6-membered ring can be unsubstituted or mono- to trisubstituted by the following radicals; halogen, nitro, cyano, hydroxyl, mercapto, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-alkylthio, amino, C1-C3-alkylamino or C1-C3-dialkylamino; nitrogen in the 5-membered ring can also be substituted by a formyl or acetyl group; R2 and R3 can be identical or different;
Y is nitrogen or CR16 where R16 is hydrogen, C1-C5-alkyl, C1-C5-alkoxy, C1-C5-alkylthio, nitro, phenyl, hydroxyl, halogen, cyano, amino, C1-C4-alkylamino, C1-C4-dialkylamino or mercapto, or CR16 forms together with R3 and its adjacent carbon atom a 5- or 6-membered ring as described above;
R4 is hydrogen, C1-C7-alkyl, C3-C7-cycloalkyl; or phenyl or naphthyl which can be substituted by one or more of the following radicals; halogen, nitro, cyano, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, phenyl, C1-C4-alkylthio, amino, C1-C4-alkylamino or C1-C4-dialkylamino,
R4 can also be a five- or six-membered heteroaromatic ring which contains one nitrogen, sulfur or oxygen atom and which can carry one or two of the following radicals: halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenoxy, C1-C4-alkylthio, C1-C4-alkylamino or C1-C4-dialkylamino;
in addition, R4 and R5 can be phenyl groups which are connected to each other in the ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2, NH or N-alkyl group;
R5 is C1-C7-alkyl, C3-C7-cycloalkyl or phenyl or naphthyl which can be substituted by from one to three of the following radicals; halogen, nitro, cyano, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, phenyl, C1-C4-alkylthio, amino, C1-C4-alkylamino or C1-C4-dialkylamino, where two radicals on adjacent carbon atoms can form together with the latter, connected via an alkylene or alkylidene group, a five- or six-membered ring in which one or more xe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x80x94 groups can be replaced by oxygen, for example: xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94;
R5 can be, for example, the following radicals: 
xe2x80x83Furthermore, R5 can be a five- or six-membered heteroaromatic ring which contains one nitrogen, sulfur or oxygen atom and which can carry one or two of the following radicals: halogen, cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenoxy, C1-C4-alkylthio, C1-C4-alkylamino or C1-C4-dialkylamino;
in addition, R5 can form together with R4 a tricyclic system as described above, and R5 can additionally be an unsubstituted or substituted phenyl or heteroaromatic radical as described above which is linked in the ortho position to R8 to form a 6-membered ring where Q must be a single bond and R8 must be a CH-R17 group;
R6 is hydrogen, C1-C4-alkyl or C1-C4-haloalkyl
Z is a single bond, oxygen, sulfur, sulfoxide xe2x80x94SOxe2x80x94 or sulfonyl;
R7 is hydrogen or C1-C4-alkyl, C2-C4-alkylene, C2-C4-alkynyl;
Q is a single bond,
a 
xe2x80x83group
R8 is hydrogen, C1-C4-alkyl, C2-C4-alkylene, phenyl or benzyl, and R8 can furthermore be directly connected to R5 as described above, in which case R8 is a CHxe2x80x94R17 group where R17 is hydrogen, C1-C4-alkyl, phenyl or phenyl which is mono- to trisubstituted by methoxy, or is one of the following radicals 
The compounds, as well as the intermediates II for preparing them, may have one or more asymmetrical substituted carbon atoms. Compounds of this type may exist as pure enantiomers or pure diastereomers or as mixture thereof. The use of an enantiomerically pure compound as active ingredient is preferred.
The invention furthermore relates to the use of the abovementioned amino acid derivatives for producing drugs, in particular for producing inhibitors of endothelin receptors.
The compounds according to the invention are prepared by reacting an amino acid derivative II with a heterocyclic derivative III where R17 is halogen or R18xe2x80x94SO2, where R18 can be C1-C4-alkyl, C1-C4-haloalkyl or phenyl. In this, R is a carboxylic ester or a carboxylic acid. II with Rxe2x95x90CO2H is preferably used. If the preparation of II results in the amino acid ester, this is first hydrolyzed to the amino acid (Rxe2x95x90CO2H) by standard methods of amino acid chemistry. 
The reaction preferably takes place in an inert solvent with the addition of a base, as described in the literature, eg. in J. Am. Chem Soc. 98 (1976) 8472-8475 or J. Chem. Soc. Perkin Trans I (1988) 691-696.
Examples of such solvents or diluents are water, aliphatic, alicyclic and aromatic hydrocarbons, which may be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol, esters such as ethyl acetate and amyl acetate, amides such as dimethylformamide and dimethylacetamide, sulfoxides and sulfones such as dimethyl sulfoxide and sulfolane, bases such as pyridine, N-methylpyrrolidone, cyclic ureas such as 1,3-dimethyl-2-imidazolidinone and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
The reaction is moreover preferably carried out at a temperature in the range from 0xc2x0 C. to the boiling point of the solvent or mixture of solvents.
It is possible to use as base an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, eg. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organo-metallic compound such as butyllithium, or an alkali metal amide such as lithium diisopropylamide.
The invention also relates to those compounds of the formula II which have not been disclosed. They can be prepared in a known manner.
The compounds IIa according to the invention, where R6xe2x95x90H and Z is a bond, can be prepared, for example, by a method described in Tetrahedron Lett. 30 (1978) 2651, by reacting a suitable imine IV with a compound V with the aid of a base in an inert solvent. This reaction is, where appropriate, carried out in a 2-phase mixture with a phase-transfer catalyst under phase-transfer conditions, for example in methylene chloride and 5-20% strength aqueous sodium hydroxide solution with a quaternary ammonium salt such as tetra-n-butylammonium bisulfate. In this, K means halogen or OR9 where R19 is methylsulfonyl, toluylsulfonyl or trifluoromethylsulfonyl. The imine VI is subsequently cleaved. 
VI can be hydrolyzed to IIa in a suitable solvent using inorganic or organic strong acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, acetic acid, trifluoromethylsulfonic acid or trifluoroacetic acid in various concentrations. Solvents which can be used are water, C1-C4-alcohols, acetonitrile, diethyl ether, tetrahydrofuran, dioxane or toluene. As a rule, the hydrolysis takes place in two stages. In the first step, VI is hydrolyzed with dilute acid to the amino acid ester IIa where R10xe2x89xa0hydrogen. Thereafter the amino acid ester is hydrolyzed with more concentrated acid or with a strong acid to the amino acid IIa where R10=H.
Reaction of compound IIa with III as described above results in compounds Ia according to the invention where R6 is hydrogen, R8 is hydrogen and Z and Q are each a single bond.
The compounds IIb according to the invention where Z is a bond, R5 is an aromatic or heteroaromatic radical and R6 is a C1-C4-alkyl group are prepared by reacting a suitable phosphonate compound VII with a carbonyl compound VIII in a Wittig-Horner reaction to give the xcex1,xcex2-unsaturated compound IX 
where R20 is C1-C6-alkyl or benzyl.
Compound IX can be converted into the carboxylic acid derivative X by a method from Chem. Ber. 64 (1931) 1493 et seq. using R5xe2x80x94H with the aid of a Friedel-Crafts catalyst such as aluminum trichloride. 
Compounds X can be converted by known methods into hydrazino acid derivatives XII as described, for example, in J. Am. Chem. Soc., 108 (1986) 6395-6397. The aminating reagent used is dialkyl azodicarboxylate XI where R21 is 2,2-dimethylethyl or benzyl. 
Hydrolysis of XII with a strong inorganic or organic acid in a suitable solvent as described above leads to the xcex1-hydrazino carboxylic acid derivative XIII. If R21 is benzyl, the conversion of XII into XIII can also take place by hydrogenolysis with hydrogen and a suitable catalyst such as palladium on active carbon of various concentrations, for example 10% palladium on carbon. 
xcex1-Hydrazino carboxylic acid derivatives XIII can be reduced with hydrogen under pressure, eg. 10-50 bar, with a suitable catalyst, eg. Raney nickel, to the xcex1-amino acid derivatives IIb. 
Compounds IIb can be reacted with III to give the compounds Ib according to the invention as described above.
Compounds IIb can also be prepared by reacting a compound XIV with a Grignard compound XV, and hydrolyzing the product XVI with acid to IIb, similar to the description in Liebigs Ann. (1977) 1174-1182: 
The compounds IIc according to the invention where R6 is C1-C4-alkyl, and Z is oxygen, sulfur, Sxe2x95x90O or SO2, can be prepared by opening a suitable aziridine XVII with an alcohol or thiol R6xe2x80x94Zxe2x80x94H to give XVIII. 
This method is described, for example, in J. Chem. Soc. Perkin Trans. II (1981) 121-126. Subsequent oxidation, eg. with metachloroperbenzoic acid in a suitable solvent, in the case where Z=sulfur provides the corresponding compounds XVIII with Zxe2x95x90SO or SO2 depending on the molar ratio of the components. R22 is hydrogen or a suitable protective group such as benzyl, benzyloxycarbonyl, tert-butyloxycarbonyl. If R22 is hydrogen, then XVIII corresponds to IIc. When R22xe2x89xa0hydrogen, the protective group must be removed by known methods of hydrolysis, with addition of acid, or hydrogenolysis with a suitable catalyst to result in compound lIe in this way. The compounds IIc according to the invention can be reacted as described above with III to give Ic.
Compounds XVII, which are likewise according to the invention, can be prepared by reacting xcex1,xcex2-unsaturated carbonyl compounds XIX which are known or have been prepared by known methods with an aminating reagent XX and a suitable catalyst, for example as disclosed in J. Org. Chem. 56 (1991) 6744-6. 
The compounds Id according to the invention where Q is a bond and R8 is not hydrogen can be prepared by converting an amino acid derivative IId (Q is a bond and R8 is hydrogen) by known methods for example into an N-benzyloxycarbonyl derivative XXI and reacting the latter 
in an inert solvent, eg. tetrahydrofuran, with a strong base, eg. potassium tert-butoxide, and an alkylating agent R8xe2x80x94K where K is normally halogen or sulfate. The derivative XXII resulting from this can be deprotected by known methods to give the amino compound IIe, for example by eliminating the benzyloxycarbonyl group with hydrogen with catalysis by palladium/active carbon in an inert solvent. 
IIe is then reacted with III to give compounds Id as described above.
The compounds Ie according to the invention where Q is a 
group can be prepared, for example, by reacting
compounds Ia-d with XXIII under basic conditions in an inert solvent to give Ie. 
In this, L is halogen, OR23 where R23 is one of the following radicals: C1-C4-alkyl, benzyl, succinimidyl or 2,4,5-trichlorophenyl; L can also be azido, p-tolylsulfonyl, methylsulfonyl, trifluoromethylsulfonyl or an anhydride moiety.
The compounds If according to the invention where R5 is linked to R8 can be prepared from the tetrahydroisoquinoline derivatives IIf, which in turn can be prepared from the amino acid derivatives IId by reacting with aldehydes of the structure XXIV in the presence of acid, eg. hydrochloric acid or sulfuric acid, similar to Synthesis (1990) 550-556. 
A {circumflex over (xe2x95x90)} aromatic or heteroaromatic system, unsubstituted or substituted
IIf is then reacted with III to give compound If as described above.
Compounds of the formula I can be obtained in enantiomerically pure form by starting from enantiomerically pure compounds II which can be prepared in enantiomerically pure and, where appropriate, diastereomerically pure form by classical racemate resolution or by enantioselective syntheses (eg. Pure Appl. Chem. 55 (1983) 1799 et seq.; Helv. Chim. Acta 71 (1988) 224 et seq.; J. Am. Chem. Soc, 110 (1988) 1547-1557; Chem. Eng. News (1989) 25-27), and reacting these compounds II with III as described above. Another possibility for obtaining enantiomerically pure compounds of the formula I is classical racemate resolution of racemic or diastereomeric compounds I with suitable enantiomerically pure bases such as brucine, strychnine, quinine, quinidine, cinchonidine, cinchonine, yohimbine, morphine, dehydroabietylamine, ephedrine (xe2x88x92), (+), deoxyephedrine (+), (xe2x88x92), threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol (+), (xe2x88x92), threo-2-(N,N-dimethylamino)-1-(p-nitrophenyl)-1,3-propanediol (+), (xe2x88x92) threo-2-amino-1-phenyl-1,3-propanediol (+), (xe2x88x92), xcex1-methylbenzylamine (+), (xe2x88x92), xcex1-(1-naphthyl)ethylamine (+), (xe2x88x92), xcex1-(2-naphthyl)ethylamine (+), (xe2x88x92), aminomethylpinone, N,N-dimethyl-1-phenylethylamine, N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine, norephedrine, norpseudoephedrine, amino acid derivatives and peptide derivatives.
Preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those in which the substituents have the following meanings:
R is a carboxylic acid, a carboxylic acid salt or a group which can be hydrolyzed to a carboxylic acid, as described above.
R2 is hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, nitro, C1-C4-alkoxy, C1-C5-alkylthio, cyano, amino, methylamino, hydroxyl or dimethylamino;
W is nitrogen, Cxe2x80x94NO2, also CH when at least one of the radicals R2, R3, R15 and R16 is a nitro group;
X is nitrogen or CR15 where R15 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, nitro, cyano, halogen or phenyl, or CR15 forms with R3 and the adjacent carbon atom a 5- or 6-membered alkylene or alkylidene ring in which one or two carbon atoms can be replaced by a hetero atom such as nitrogen, oxygen or sulfur, and which can be mono- or disubstituted by a C1-C3-alkyl (or C1-C3-alkoxy group); nitrogen in a 5-membered ring may additionally be substituted by a CHO or COCH3 group;
R3 can have the same meaning as R2 and additionally form with X and the adjacent carbon atom an unsubstituted or substituted 5- or 6-membered ring as described above; R3 can furthermore form with the adjacent carbon atom and Y a 5- or 6-membered alkylene or alkylidene ring in which one or two carbon atoms can be replaced by nitrogen, oxygen or sulfur and which can be mono- or disubstituted by a C1-C3-alkyl or C1-C3-alkoxy group, and a nitrogen atom in a 5-membered ring can be substituted by a CHO or COCH3 group;
R4 has the meaning of hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl or phenyl which can be substituted by one or more of the following radicals: halogen, C1-C4-alkyl, C1-C4-alkoxy, phenyl, furthermore R4 and R5 can be phenyl groups which are connected to each other in the ortho positions by a direct linkage, a CH2 group, a CH2xe2x80x94CH2 group or an oxygen atom;
R5 can have the same meaning as R4 apart from hydrogen and C1-C6-alkyl, R5 can additionally be phenyl which can be substituted exclusively or in addition to the abovementioned radicals by two radicals on adjacent carbon atoms, which together represent a 1,3-dioxomethylene or 1,4-dioxoethylene group and form with the adjacent carbon atoms a 5- or 6-membered ring;
R6 is hydrogen or C1-C4-alkyl;
Z is a single bond, oxygen or sulfur;
R7 is hydrogen or C1-C4-alkyl;
Q is single bond, a carbonyl group or an oxycarbonyl group;
R8 is hydrogen or C1-C4-alkyl.
Particularly preferred compounds of the formula I, both as pure enantiomers or pure diastereomers or as mixture thereof, are those in which the substituents have the following meanings:
R is a carboxylic acid, a carboxylic acid salt or a group which can be hydrolyzed to a carboxylic acid, as described above;
R2 is hydrogen, chlorine, methyl, ethyl, CF3, nitro, methoxy, ethoxy, hydroxyl, methylthio, amino, N-methylamino or dimethylamino;
W is nitrogen;
X is nitrogen or CR15 where R15 is hydrogen, methyl, nitro or cyano, or CR15 forms with R3 and the adjacent carbon atom a 5- or 6-membered alkylene or alkylidene ring in which one carbon atom can be replaced by oxygen, and which can be substituted by a methyl or methoxy group; the 5- or 6-membered alkylene or alkylidene ring can have the following structures, for example: 
R3 can have the same meaning as R2 and additionally form with X and the adjacent carbon atom an unsubstituted or substituted 5- or 6-membered ring as described above; R3 can furthermore form with the adjacent carbon atom a substituted or unsubstituted 5- or 6-membered alkylene or alkylidene ring in which one or two carbon atoms can be replaced by nitrogen or oxygen and which can be substituted by a methyl or methoxy group; examples of such alkylene or alkylidene rings are: 
R4 has the meaning of hydrogen, methyl, ethyl, n-propyl, 1-methylethyl, cyclohexyl, or phenyl which can be substituted by one or two methoxy groups, furthermore R4 and R5 can be phenyl groups which are connected to each other in the ortho positions by a direct linkage, a CH2 or CH2-CH2 group;
R5 is cyclohexyl or phenyl which can be substituted by phenyl, one to three methoxy groups, or exclusively or in addition to a methoxy group by two radicals on adjacent carbon atoms which together represent a 1,3-dioxomethylene or 1,4-dioxoethylene group and form with the adjacent carbon atoms a 5- or 6-membered ring, R5 can additionally be an unsubstituted or substituted phenyl ring which is linked in the ortho position to R8 to form a 6-membered ring when Q is a single bond and R8 is a CHxe2x80x94R17 group;
R6 is hydrogen, methyl, ethyl, n-propyl or 1-methylethyl;
R7 is hydrogen or methyl;
Q is a single bond, a carbonyl group or an oxycarbonyl group;
R8 is hydrogen, methyl or 1,1-dimethylethyl, R8 can additionally be directly connected to R5 as described above when R8 is a CHxe2x80x94R17 group in which R17 is hydrogen, methyl, ethyl, phenyl or phenyl which is mono- to trisubstituted by methoxy, or one of the following radicals: 
The compounds of the present invention provide a novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, acute kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis following angioplasty, benign prostate hyperplasia, ischemic kidney failure and that caused by intoxication, and hypertension.
The good effect of the compounds can be shown in the following tests:
Receptor Binding Studies
Cloned human ETA receptor-expressing CHO cells and guinea-pig cerebellar membranes with  greater than 60% ETB by comparison with ETA receptors were used for the binding studies.
Membrane Preparation
The ETA receptor-expressing CHO cells were grown in F12 medium containing 10% fetal calf serum, 1% glutamine, 100 U/ml penicillin and 0.2% streptomycin (Gibco BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. The F12 medium was then neutralized, and the cells were collected by centrifugation at 300xc3x97g. To lyse the cells, the pellet was briefly washed with lysis buffer (5 mM tris-HCl, pH 7.4 with 10% glycerol) and then incubated at a concentration of 107 cells/ml of lysis buffer at 4xc2x0 C. for 30 min. The membranes were centrifuged at 20,000xc3x97g for 10 min, and the pellet was stored in liquid nitrogen.
Guinea-pig cerebella were homogenized in a Potter-Elvejhem homogenizer and obtained by differential centrifugation at 1,000xc3x97g for 10 min and repeated centrifugation of the supernatant at 20,000xc3x97g for 10 min.
Binding Assays
For the ETA and ETB, receptor binding assays, the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4 with 5 mM MnCl2, 40 xcexcg/ml bacitracine and 0.2% BSA) at a concentration of 50 xcexcg of protein per assay mixture, and incubated with 25 pM 125I-ET1, (ETA receptor assay) or 25 pM 125I-RZ3 (ETB receptor assay) at 25xc2x0 C. in the presence and absence of test substance. The non-specific binding was determined using 10xe2x88x927 M ET1. After 30 min, the free and bound radioligand were separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway), and the filters were washed with ice-cold tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.
Functional in vitro assay system for searching for endothelin receptor (subtype A) antagonists
This assay system is a functional, cell-based assay for endothelin receptors. When certain cells are stimulated with endothelin 1 (ET1) they show an increase in the intracellular calcium concentration. This increase can be measured in intact cells loaded with calcium-sensitive dyes.
Fibroblasts which had been isolated from rats and in which an endogenous endothelin receptor of subtype A had been detected were loaded with the fluorescent dye Fura 2-an as follows: After trypsinization, the cells were resuspended in buffer A (120 mM NaCl, 5 mM KCl, 1.5 mM MgCl2, 1 mM CaCl2, 25 mM HEPES, 10 mM glucose, pH 7.4). to a density of 2xc3x97106/ml and incubated with Fura 2-am (2 xcexcM), Pluronic F-127 (0.04%) and DMSO (0.2%) at 37xc2x0 C. in the dark for 30 min. The cells were then washed twice with buffer A and resuspended at 2xc3x97106/ml.
The fluorescence signal from 2xc3x97105 cells per ml with Ex/Em 380/510 was recorded continuously at 30xc2x0 C. To the cells were added the test substances and after an incubation time of 3 min ET1. The maximum change in fluorescence was determined over 30 minutes. The response of the cells to ET1 without previous addition of a test substance served as control and was set equal to 100%.
In vivo Testing of ET Antagonists
Male SD rats weighing 250-300 g were anesthetized with amobarbital, artifically ventilated, vagotomized and pithed. The carotid artery and jugular vein were cathetized.
Intravenous administration of 1 xcexcg/kg ET1 to control animals leads to a marked rise in blood pressure which persists for a lengthy period.
The test compounds were injected i.v. (1 ml/kg) into the test animals 5 min before ET1 administration. To determine the ET-antagonistic properties, the rise in blood pressure in the test animals was compared with that in the control animals.
Sudden Death of Mice Induced by Endothelin-1
The principle of the test is the inhibition of the sudden heart death of mice caused by endothelin, probably owing to constriction of the coronary vessels, by pretreatment with endothelin receptor antagonists. Intravenous injection of 10 nmol/kg endothelin in a volume of 5 ml/kg of body weight is followed within a few minutes by the death of the animals.
The lethal dose of endothelin-1 is checked in each case on a small group of animals. Intravenous administration of the test substance is usually followed after 5 min by the injection of endothelin-1 which was lethal in the reference group. The times before administration increase with other modes of administration, possibly up to several hours.
The survival rate is recorded, and effective doses which protect 50% of the animals from endothelin-induced heart death for 24 h or longer (ED 50) are determined.
Functional Test on Vessels for Endothelin Receptor Antagonists
First a contraction is induced by K+ in segments of rabbit aorta after a previous tension of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37xc2x0 C. and pH 7.3-7.4. Washing out is followed by construction of an endothelin dose-effect plot up to the maximum.
Potential endothelin antagonists are administered to other preparations of the same vessel 15 min before starting the endothelin dose-effect plot. The effects of endothelin are calculated as a % of the K+-induced contraction. Effective endothelin antagonists result in a shift in the endothelin dose-effect plot to the right.
The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.
The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active ingredient is about 0.5-50 mg/kg of body weight on oral administration and about 0.1-10 mg/kg of body weight on parenteral administration.
The novel compounds can be used in conventional solid or liquid pharmaceutical forms, eg. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. For this purpose the active ingredients can be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellent gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain from 0.1 to 90% by weight of active ingredient.